Polyamines, spermine/spermidine (SPM/SPD), are accumulated in glial cells in CA1 area of hippocampus and if released to neurons (known to contain receptors and channels sensitive to SPM/SPD) could regulate the neuronal network. Our preliminary data lead to a novel proposition of the glial-neuronal relationship based upon polyamine exchange. Our working hypothesis is that SPM/SPD released from depolarized glia has three different actions on AMPA receptors, GABA receptors, and Kir channels. A transient fall of [H+]o and [Ca2+]o together with increased [K+]o during neuronal excitation will facilitate the effect of endogenous SPM on neuronal and glial receptors and channels. Our preliminary results obtained with the help of a novel method of non-enzymatic cell isolation support this hypothesis: (1) SPM at submillimolar concentration inhibits at extracellular sites both GluR2-lacking AMPA receptors (Ca2+ permeable) of interneurons and the GABAA receptor depolarizing overshoot of pyramidal cells, responsible for inhibitory feedback in the brain. (2) SPM together with a fall of [H+]o and [Ca2+]o reduces this feedback dramatically. (3) In contrast, SPM potentiates GluR2-rich AMPA receptors (Ca2+ impermeable) on a sub-population of pyramidal cells (PC), thus, SPM facilitates excitation of PC. (4) At higher doses SPM depresses AMPA receptors of PC as well This finding is related to the behavior of neurons in slices. (5) Submillimolar concentrations of selective glial inhibitors, that release/deplete SPM/SPD from glia, produce paired-pulse facilitation (PPF), suggesting that glia (found together with inhibitory interneurons) play a crucial role in inhibitory transmission. In addition, (6) SPM/SPD released from glia may decrease neuronal Ca2+ entry through AMPA and NMDA receptors and may protect neurons against Ca2+-damage. (7) Loss of SPM in glia leads to relief of rectification of glial K+-inwardly rectifying (Kir) channels, this may additionally protect neurons by removal of excess [K+]o from brain to blood vessels, the "sinks" to which astrocytes are attached by endfeet. Thus, spermine is one of the major links between glia and neurons. These findings will contribute to understanding the role of glial cells and to minimizing post-stroke damage.